{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T11:55:36Z","timestamp":1753876536575,"version":"3.41.2"},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:00Z","timestamp":1747094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000765","name":"University College London","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000765","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University College London Hospitals & Barts Biomedicine NIHR"},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Stephen Lyness Memorial Fund"},{"name":"NIHR Integrated Academic Training programme"},{"DOI":"10.13039\/501100023392","name":"NIHR Barts Biomedical Research Centre","doi-asserted-by":"publisher","award":["NIHR203330"],"award-info":[{"award-number":["NIHR203330"]}],"id":[{"id":"10.13039\/501100023392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019287","name":"Barts Health NHS Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019287","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009148","name":"Queen Mary University of London","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009148","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015092","name":"St George's University Hospitals NHS Foundation Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100015092","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004337","name":"St. George's, University of London","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004337","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007155","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N025083\/1","RYC2021-031413-I"],"award-info":[{"award-number":["MR\/N025083\/1","RYC2021-031413-I"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union \u201cNextGenerationEU\/PRTR\u201d","award":["MCIN\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MCIN\/AEI\/10.13039\/501100011033"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Familial progressive cardiac conduction disease (PCCD) is a heritable condition leading to conduction defects that may require pacemaker implantation. The penetrance of rare PCCD variants in general populations and relationship with electrocardiogram (ECG) trait polygenic risk scores (PRS) is unknown. We investigated the prevalence and phenotypic expression of rare variants linked with PCCD in a population cohort and to establish whether ECG-trait PRSs improve risk prediction.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Carriers of known rare pathogenic\/likely pathogenic (P\/LP) PCCD variants, and variants of uncertain significance (VUS) were identified in 469 511 UK Biobank participants. Primary (any conduction disease) and secondary (high-grade AV block and pacemaker implantation) outcomes were evaluated in lifetime-risk Cox proportional hazard models including rare variant status, sex, and age. Additional models including PR and QRS PRSs were tested. There were 25 P\/LP carriers (5 genes) and 3174 VUS carriers (4 genes). Conduction disease was more prevalent in P\/LP individuals compared with non-carriers (28% vs. 5.3%, P &amp;lt; 0.001) with a hazard ratio (HR) of 6.60 (95% CI = 3.14\u201313.8) over 6.5 million person-years of follow-up and C-index 0.602 (0.599\u20130.605). This was driven by AV block (HR 23.2 [8.7\u201361.8]) and pacemaker implantation (HR 13.4 [6.01\u201329.8]). All individuals were aged &amp;gt;50 at diagnosis. Combined with P\/LP status, PR-PRS and QRS-PRS improved model performance (C-index 0.618 [0.615\u20130.622]).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>In a population-based cohort, PCCD P\/LP variant carriers were at greater risk of conduction disease. Including PRSs for the PR and QRS improved risk prediction, supporting the combination of rare and common variants in risk assessment.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/europace\/euaf103","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T17:52:16Z","timestamp":1747158736000},"source":"Crossref","is-referenced-by-count":0,"title":["Phenotypic expression of rare progressive cardiac conduction disease variants in the general population"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3212-7706","authenticated-orcid":false,"given":"Ravi A","family":"Shah","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular Science, University College London , Rayne Building, University Street, London WC1E 6BT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4130-5866","authenticated-orcid":false,"given":"Julia","family":"Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Centre for Clinical Pharmacology and Precision Medicine, Queen Mary University of London , Charterhouse Square, London EC1M 6BQ ,","place":["UK"]},{"name":"Aragon Institute of Engineering Research, University of Zaragoza , Zaragoza ,","place":["Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red\u2013Bioingenier\u00eda, Biomateriales y Nanomedicina , Zaragoza ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0283-6376","authenticated-orcid":false,"given":"Claire","family":"Kirkby","sequence":"additional","affiliation":[{"name":"Barts Heart Centre, St Bartholomew\u2019s Hospital , W Smithfield, London EC1A 7BE ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Ives","sequence":"additional","affiliation":[{"name":"Barts Heart Centre, St Bartholomew\u2019s Hospital , W Smithfield, London EC1A 7BE ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Lowe","sequence":"additional","affiliation":[{"name":"Barts Heart Centre, St Bartholomew\u2019s Hospital , W Smithfield, London EC1A 7BE ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4176-2947","authenticated-orcid":false,"given":"Patricia B","family":"Munroe","sequence":"additional","affiliation":[{"name":"Centre for Clinical Pharmacology and Precision Medicine, Queen Mary University of London , Charterhouse Square, London EC1M 6BQ ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9055-9267","authenticated-orcid":false,"given":"Pier D","family":"Lambiase","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Science, University College London , Rayne Building, University Street, London WC1E 6BT ,","place":["UK"]},{"name":"Barts Heart Centre, St Bartholomew\u2019s Hospital , W Smithfield, London EC1A 7BE ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9831-6817","authenticated-orcid":false,"given":"William J","family":"Young","sequence":"additional","affiliation":[{"name":"Centre for Clinical Pharmacology and Precision Medicine, Queen Mary University of London , Charterhouse Square, London EC1M 6BQ ,","place":["UK"]},{"name":"Barts Heart Centre, St Bartholomew\u2019s Hospital , W Smithfield, London EC1A 7BE 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